Encapsulated calcium acetate caplet and amethod for inhibiting gastrointestinal phosphorous absorption

ABSTRACT

A composition for inhibiting gastrointestinal absorption of phosphorous in an individual dividual. The composition includes a quantity of calcium acetate sufficient to bind the phosphorous in the gastrointestinal tract of the individual. The calcium acetate has a bulk density of between 0.50 kg/L and 0.80 kg/L and is dimensioned to form a caplet for fitting within a capsule in a manner that optimizes the volume of the capsule. Also provided is a method for administering the calcium acetate composition of the present invention to an individual to reduce phosphorous absorption by binding with the phosphorous in their gastrointestinal tract.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The present invention relates to the field of oral pharmaceuticalcompositions. More particularly, the present invention relates to anencapsulated calcium acetate caplet, and to a method for binding andinhibiting gastrointestinal absorption of phosphorous using anencapsulated calcium acetate caplet.

[0003] 2. Background Information

[0004] A major focus of research and development efforts in thepharmaceutical industry is on the formulation of acceptable oralpharmaceutical compositions. More particularly, these efforts areconcentrated on making oral pharmaceuticals that are palatable to theconsumer. Chief among the concerns of pharmaceutical manufacturers inthis area is the development of drugs that are as palatable as they areefficacious. The importance of these research efforts is greatest wherethe pharmaceuticals at issue are intended to ameliorate a patient'smedical condition or alleviate their symptoms in cases of terminalillness. Chronic renal failure is one example of such an illness.

[0005] In cases of chronic renal failure, hyperphosphatemia, or excessphosphorus retention, plays a major role in the development of secondaryhyperparathyroidism and osteodystrophy. Antacids or prescriptionmedications are commonly used to manage or prevent hyperphosphatemia bybinding dietary phosphorus and, thus, preventing its absorption into thegastrointestinal tract.

[0006] Phosphorous binders bind phosphorus in the form of a phosphorousion within the stomach and intestines. This process is thought to resultfrom a chemical reaction between dietary phosphorus and the cationpresent in the binder compound. The reaction causes the formation ofinsoluble and hence unabsorbable phosphate compounds. The cation in somephosphorous binders is aluminum or calcium. Despite their capacity forbinding phosphorous, large quantities of antacids must be ingested overa long period of time for them to be effective. Therefore, dosage sizeand palatability are particularly important for patients with chronicrenal disease.

[0007] Prescription medications typically effective in managing orpreventing hyperphosphatemia include calcium acetate. Calcium acetatetreatment is one of the most effective methods for management of chronicrenal disease. When administered orally, calcium acetate is moreeffective than any other calcium-containing binder in bindingphosphorus. Used alone or in combination with other materials, calciumacetate binds phosphorus in the gastrointestinal tract and reduces thepercentage of consumed phosphorus (i.e., of a given “dose” ofphosphorus) which is absorbed into the bloodstream. This compound ismost effective in reducing phosphorous absorption when it isadministered close in time to food consumption. Despite these benefits,calcium acetate treatments heretofore known in the art have not beenwithout their drawbacks.

[0008] Calcium acetate is a naturally occurring solid. Like most solidsfound in nature, the bulk density of calcium acetate varies according toits source. Bulk density is the density, typically of a solid, as pouredor passively filled into a measurement device. Bulk density can bedetermined by measuring the volume of a known mass (i.e., 125 g) ofpowder that has been passed into a graduated cylinder, followed by five“tamps” of the cylinder from a height of one (1) inch. Alternatively, itmay be determined by measuring that volume of the known mass that hasbeen passed through a volume measuring apparatus into a cup. Whiledensities are normally expressed in grams per cm³, where measured ingraduated cylinders, the bulk density of powder volumes are expressed ingrams per mL, where cm³ and mL are equivalent volume units.

[0009] United States Pharmacopoeia (USP) is a widely recognizedorganization that sets some of the standards that pharmaceuticalmanufacturers must meet to sell their drugs and drug compounds in theUnited States. USP standards include procedures for the physical teststhat must be performed on drugs and drug compounds to ensure compliancewith the specific requirements set forth within these standards. USP #24defines some of these standards for calcium acetate tablets. Forexample, physical test #711 on page 1941 of USP #24 sets forth the testto determine compliance with the dissolution standard set forth forcalcium acetate tablets. USP #24 and #711 are incorporated herein byreference.

[0010] Pharmaceutical manufacturers in the art have heretofore usedcalcium acetate raw materials to form calcium acetate medicationswithout regard to the density of the raw material fractions used. Theresult of this practice is that the manufacturers have been unable toproduce a calcium acetate capsule or tablet of the usual dosage amountthat is less than #00 in size, while passing test #711. An unfortunateconsequence of the intrinsic characteristics of calcium acetate, and thepractice of the pharmaceutical industry, is that patients needing thismedication, such as end stage renal disease patients have heretoforefound such medications due to their bulk size difficult to swallow. Asecond, equally undesirable characteristic of calcium acetate is that ithas a chalky taste that is very unpleasant to the palate and isdifficult to mask. Consequently, despite the obvious benefits of calciumacetate-based treatments, patients would typically fail to take theproper doses of their medicine, or turn to antacids as an alternative tothese difficult-to-swallow unpalatable medications.

[0011] Calcium acetate compositions were heretofore no more desirabledue to the dosing sizes, dosing requirements and the unpleasant tasteassociated with consumption of these medications. Accordingly, anencapsulated caplet that provides an effective dosage of medication forthe treatment and management of terminal illnesses, without the risk ofdosage side effects, is desired. An encapsulated caplet that also sealsthe taste of the medication and compresses the medication to ease orreduce the dosage volume necessary for effective illness treatment ormanagement is desired, as well.

SUMMARY OF THE INVENTION

[0012] The present invention relates to a composition for bindingphosphorous within the gastrointestinal tract of an individual and,thus, reducing phosphorus absorption in an individual's intestine. Thepresent invention also relates to a method for binding phosphorous inthe gastrointestinal tract of an individual to reduce phosphorousabsorption therefrom. Moreover, the present invention relates to amethod for reducing serum phosphate levels, since phosphorous is boundin the gastrointestinal tract and phosphorous absorption is lower thanwould otherwise occur. The composition and method of the presentinvention are particularly useful in the treatment and prevention ofhyperphosphatemia in individuals with end stage renal disease. Thecomposition and method of the present invention are also useful in thetreatment and prevention of any other disease in which the ability toexcrete phosphorus from the body (e.g., in the urine) is impaired.

[0013] The composition of the present invention includes a quantity ofcalcium acetate, having a specific bulk density range, that issufficient to bind the phosphorous in the gastrointestinal tract of anindividual. The calcium acetate composition is dimensioned to form acaplet for fitting within a capsule in a manner that optimizes thevolume of the capsule, i.e., fills the internal volume of the capsulesubstantially completely. Insertion of the calcium acetate compositionwithin the capsule masks the unpleasant and unpalatable taste of theenclosed caplet.

[0014] The method of the present invention comprises administering thecalcium acetate composition, in the caplet-within-capsule form, to anindividual to bind with the phosphorous in their gastrointestinal tract.Administration of the calcium acetate composition of the presentinvention according to the method described herein is associated withenhanced patient compliance and fewer side effects than is evident inadministering presently available calcium acetate medications andphosphorus binders. This improved patient compliance withphosphate-binding ingestion will improve management of the diseaseprocess.

DETAILED DESCRIPTION OF AN ILLUSTRATIVE EMBODIMENT

[0015] The present invention takes advantage of the surprising discoverythat, by selecting calcium acetate raw materials within a particularrange of bulk densities, it is possible to compress and dimension theraw material to form a calcium acetate caplet, capsule or tablet that issmaller than heretofore formed and is more easily ingested. Moreparticularly, the selection of a particular density range of calciumacetate permits the compression and dimensioning of the raw material toform a caplet that optimally fits within and substantially completelyfills a capsule.

[0016] The present invention relates to an orally administrable calciumacetate composition that is useful in reducing phosphorus absorption inthe gastrointestinal tract. More particularly, the composition consistsof a quantity of calcium acetate having a bulk density of between 0.50kg/L and 0.80 kg/L that dissolves by at least 85% in less than 15minutes as specified in USP #24 at 50 to 100 RPM, apparatus 1 or 2,using purified water as diluent. As set forth in Table 1, a calciumacetate composition having a bulk density of between 0.55 kg/L and 0.75kg/L is desirable as it has optimal pharmaceutical properties, includingcompliance with USP #24. More preferably, the bulk density of thecalcium acetate used in the composition of the present invention isbetween 0.60 kg/L and 0.70 kg/L, and the dosage amount is equivalent toapproximately 667 mg, or approximately 333.3 mg, as desired, in a size#0 or size #2 capsule, respectively. Table 1 Displays Bulk Density MeetsCaplet Tablet Displays Tablet Passes (kg/L) Target Weight CappingPicking Dissolution <0.55 No Yes Yes No 0.55 to 0.75 Yes No No Yes >0.75Yes Yes No No

[0017] As illustrated in this table, column 2 indicates whether acalcium acetate caplet of a given bulk density can be compressed to meetthe target weight of 667 mg and fit into a #0 or a target weight of333.5 mg in a #2 size capsule. Column 3 indicates whether the calciumacetate caplet of the noted bulk density can be compressed to meet atarget weight of 667 mg and fit into a #0 capsule, or a target weight of333.5 mg in fit into a #2 size capsule, without an unacceptableincidence of “capping” (i.e., splitting along a plane parallel to thelong axis of the capsule). Column 4 indicates whether the calciumacetate caplet of the given bulk density can be compressed to meet atarget weight of 667 mg and fit into a #0 capsule, or a target weight of333.5 mg in fit into a #2 size capsule, without an unacceptableincidence of “picking” (i.e., loss of small punctuate flecks of materialfrom its surface). Column 5 indicates whether the calcium acetate capletof the given bulk density will pass the dissolution specifications forcalcium acetate upon being compressed to a size to fit 667 mg into a #0or 333.5 mg into a #2 size capsule. Throughout this discussion, 667 mgand 333.5 mg refer to calcium acetate, anhydrous basis. An equivalentamount of calcium acetate monohydrate basis weighs 708 mg or 354 mg,respectively.

[0018] The calcium acetate composition of the present invention isoptionally dimensioned to form a delivery vehicle comprising a tablet, acapsule or a caplet. Of these delivery vehicles, capsules are preferredas they completely coat and envelop the caplet until the capsule reachesthe gastrointestinal tract, or stomach. Once within the stomach, thecapsule shell is dissolved and the medication is released and binds thephosphorous in the intestine.

[0019] The capsule is formed from any material which, when wetted by theindividual's saliva or by accompanying water or other flushing fluid,facilitates the ingestion of the caplet. More preferably, the capsuleshell consists of a gelatin material as a gelatin capsule better masksthe bitter taste of the calcium acetate medication. The gelatin capsuleis also preferred as it provides a more palatable surface to themedication that makes it easier to swallow and pass into the digestivesystem.

[0020] In one embodiment, the calcium acetate is dimensioned to form acaplet for fitting within a volume defined by a #0 size capsule in amanner that optimizes the volume of the capsule, i.e., fills theinternal volume of the capsule substantially completely. In anotherembodiment, the calcium acetate is dimensioned to form a caplet forfitting within and substantially completely filling a volume defined bya #2 size capsule.

[0021] The composition of the present invention preferably consists ofapproximately 667 mg of calcium acetate dimensioned to form a caplet forfitting within a volume defined by #0 size capsule in a manner thatoptimizes the volume of the capsule. In another embodiment, thecomposition preferably consists of approximately 333.5 mg of calciumacetate dimensioned to form a caplet for fitting within andsubstantially completely filling a volume defined by #2 size capsule.

[0022] The present invention also relates to a method of inhibitinggastrointestinal phosphorus absorption. More particularly, the method ofthe present invention facilitates the oral administration of calciumacetate to effectively bind with phosphorus in an individual'sgastrointestinal tract, and reduce the serum absorption of phosphorous.Additionally, the method of the present invention facilitates thereduction in phosphorous absorption that is noted when the compositionis consumed at or near mealtime, the time at which foods and beveragesare ingested.

[0023] Administering the calcium acetate composition of the presentinvention will also reduce the absorption of dietary phosphorus, therebyreducing the risks of adverse effects (e.g., bone disease and secondaryhyperparathyroidism) observed in individuals (e.g., chronic renalpatients) in whom the ability to excrete phosphorus in the urine isimpaired.

[0024] According to the method of the present invention, a quantity ofcalcium acetate having a bulk density of between 0.50 kg/L and 0.80 kg/Lis administered in sufficient quantities to reduce phosphorus absorptionin the gastrointestinal tract. The calcium acetate is administeredorally, and is preferably dimensioned to form a caplet for fittingwithin a capsule in a manner that optimizes the volume of the capsule.The caplet dissolves in less than 15 minutes at 50 to 100 RPM, apparatus1 or 2, in purified water (USP #24).

[0025] The foregoing description has been directed to specificembodiments of this invention. It will be apparent, however, that othervariations and modifications may be made to the described embodimentswith the attainment of some or all of their advantages. Accordingly,this description should be taken only by way of example and not by wayof limitation. It is the object of the appended claims to cover all suchvariations and modifications as come within the true spirit and scope ofthe invention.

[0026] Additional excipients, fillers, dispersants, lubricants and thelike may be added to the composition of the present invention to improveits manufacture, and such modifications will be recognized as beingwithin thew spirit and the scope of the present invention.

What is claimed is:
 1. A composition for binding phosphorous within thegastrointestinal tract of an individual, the composition comprising: aquantity of calcium acetate sufficient to bind the phosphorous in thegastrointestinal tract of the individual, the calcium acetate having abulk density of between 0.50 kg/L and 0.80 kg/L and being dimensioned toform a caplet for fitting within a volume defined by capsule in a mannerwhich optimizes the volume of the capsule.
 2. The composition of claim1, wherein the quantity of calcium acetate is a dosage amount equivalentto approximately 667 mg of calcium acetate, anhydrous basis.
 3. Thecomposition according to claim 1 wherein the calcium acetate is intablet form.
 4. The composition of claim 1, wherein the calcium acetatehas a bulk density of between 0.55 kg/L and 0.75 kg/L.
 5. Thecomposition of claim 1, wherein the calcium acetate has a bulk densityof between 0.60 kg/L and 0.70 kg/L.
 6. The composition of claim 1,wherein the calcium acetate dissolves by at least 85% in not less than15 minutes USP #24 at 50 to 100 RPM, apparatus 1 or
 2. 7. Thecomposition of claim 1, wherein the calcium acetate is dimensioned toform a caplet for fitting within a volume defined by #0 size capsule ina manner that optimizes the volume of the capsule.
 8. The composition ofclaim 7, wherein 667 mg of anhydrous calcium acetate are dimensioned toform the caplet for fitting within the volume defined by #0 sizecapsule.
 9. The composition of claim 7, wherein 708 mg of monohydrouscalcium acetate are dimensioned to form the caplet for fitting withinthe volume defined by #0 size capsule.
 10. The composition of claim 1,wherein the calcium acetate is dimensioned to form a caplet for fittingwithin a volume defined by #2 size capsule in a manner that optimizesthe volume of the capsule.
 11. The composition of claim 10, wherein333.3 mg of anhydrous calcium acetate are dimensioned to form the capletfor fitting within the volume defined by #2 size capsule.
 12. Thecomposition of claim 7, wherein 354 mg of monohydrous calcium acetateare dimensioned to form the caplet for fitting within the volume definedby #2 size capsule.
 13. A composition for absorbing phosphorous withinthe gastrointestinal tract of an individual, the composition comprisingapproximately 667 mg of calcium acetate dimensioned to form a caplet forfitting within a volume defined by #0 size capsule in a manner whichoptimizes the volume of the capsule.
 14. A composition for absorbingphosphorous within the gastrointestinal tract of an individual, thecomposition comprising approximately 333.5 mg of calcium acetatedimensioned to form a caplet for fitting within a volume defined by #2size capsule in a manner which optimizes the volume of the capsule. 15.A method for binding phosphorous in the gastrointestinal tract of anindividual, the method comprising at least the step of: administering acomposition for binding phosphorous, the composition comprising aquantity of calcium acetate sufficient to bind with the phosphorous inthe gastrointestinal tract of the individual, the calcium acetate havinga bulk density of between 0.60 kg/L and 0.80 kg/L and being dimensionedto form a caplet for fitting within a capsule in a manner whichoptimizes the volume of the capsule.
 16. The method of claim 15, whereinthe calcium acetate has a bulk density of between 0.55 kg/L and 0.75kg/L.
 17. The method of claim 15, wherein the calcium acetate has a bulkdensity of between 0.60 kg/L and 0.70 kg/L.
 18. The method of claim 15,wherein the calcium acetate dissolves in less than 15 minutes accordingto USP #24, Test 711 at 50 to 100 RPM, apparatus 1 or 2.